The recent outbreaks of disease associated with infection by the hantavirus Sin Nombre and the filovirus Ebola are causes for concern. Small changes in these viruses affecting transmissibility or virulence could lead to devastating epidemics. Panels of human antibodies to these viruses can be a very valuable resource, both in terms of current viruses and variants that may arise in the future. We propose to use antibody phage library technology to generate these panels. In this technology, antibody repertoires are rescued from humans and cloned into bacteriophage display vectors to generate vast antibody libraries. Affinity selection on immobilized antigen allows the retrieval of specific antibodies. The unique strengths of the technology for this project are (a) the ability to select, possibly rare, highly potent human antibodies from immune donors and evolve these antibodies in vitro to be still more effective and (b) the ability to exquisitely target selection to yield broad reactivities across a wide variation in virus phenotype. The latter is particularly important to be able to respond to new emerging viral strains. We propose that the antibodies generated in this project will find application as immunoprophylactic and immunotherapeutic reagents, will be valuable in guiding vaccine design and will be useful as analytical reagents. The studies carried out to date on murine antibodies to the hantaviruses, Hantaan and Puumala, provide strong indicators for the strategy to be pursued and the likelihood of success for Sin Nombre virus. Ebola virus is a more difficult problem but the principle of whether or not monoclonal antibodies can be used against filoviruses needs to be established.